To determine differences in post-treatment QoL across treatment settings in patients receiving adjuvant radiation therapy for head and neck squamous cell carcinoma (HNSCC). This was a prospective observational cohort study of patients with HNSCC initially evaluated in a head and neck surgical oncologic and reconstructive clinic at an academic medical center (AMC). Participants were enrolled prior to treatment in a prospective registry collecting demographic, social, and clinical data. Physical and social-emotional QoL (phys-QoL and soc-QoL, respectively) was measured using the University of Washington-QoL questionnaire at pre-treatment and post-treatment visits. A cohort of 177 patients, primarily male and White with an average age of 61.2 ± 11.2 years, met inclusion criteria. Most patients presented with oral cavity tumors (n = 132, 74.6%), had non-HPV-mediated disease (n = 97, 61.8%), and were classified as Stage IVa (n = 72, 42.8%). After controlling for covariates, patients treated at community medical centers (CMCs) reported a 7.15-point lower phys-QoL compared with those treated at AMCs (95% CI: -13.96 to -0.35, p = 0.040) up to 12 months post-treatment. Additionally, patients who were treated at CMCs had a 5.77-point (-11.86-0.31, p = 0.063) lower soc-QoL score compared with those treated at an AMC, which was not statistically significant. This study revealed that HNSCC patients treated with radiation at AMCs reported significantly greater phys-QoL in their first-year post-treatment compared to those treated at CMCs, but soc-QoL did not differ significantly. Further observational studies are needed to explore potential factors, including treatment planning and cancer resource engagement, behind disparities between AMCs and CMCs. 3 Laryngoscope, 134:3645-3655, 2024.